LUNG-ON-A-CHIP PULMONARY FIBROSIS MODEL FOR DRUG DISCOVERY PROJECT SUMMARY Pulmonary fibrosis (PF) is a devastating disease characterized by excessive extracellular matrix (ECM) accumulation and associated scar formation that compromises breathing function and often leads to respiratory failure and death. There are multiple etiologies of PF, including environmental particles, radiation, and even certain antibiotics, but in most cases patients are diagnosed with idiopathic pulmonary fibrosis (IPF) where the specific trigger is unknown. There is no cure for IPF as current treatments are only capable of slowing lung damage, and prognosis is poor, with a median survival time of 2.5 to 3.5 years after diagnosis. A significant barrier to the development of PF therapeutics is interspecies differences in lung physiology and associated inflammatory and immune responses such that animal models do not sufficiently recapitulate certain aspects of the disease. Recent advances in human organs-on-chip (Organ Chip) microfluidic culture systems that recapitulate the multicellular architecture, tissue-tissue interfaces, mechanical environment (e.g., cyclic breathing motions), and vascular perfusion of major organ functional units have allowed for physiologically based evaluation of cell, environmental, and drug interactions within an organ-level context in vitro. We can utilize these Organ Chips to gain complementary data to animal models about the role of specific cellular contributions to PF development. Thus, the main goal of this proposal is to develop a human Organ Chip model of PF to better understand the mechanism of fibrosis development and progression, and to discover potential new therapeutics that could slow disease progression or reverse this deadly disease. This goal will be achieved with the following two aims: human PF Chips will be engineered with myofibroblasts from healthy donors and PF patients, with the addition of various environmental stimuli as well as potential inflammatory and immune contributors implicated in PF development (Aim 1), and transcriptomics data from these PF Chips will be compared to existing genomics literature data to identify drugs to use as potential PF therapeutics, prioritizing for clinically approved drugs that can be repurposed (Aim 2). This approach is innovative because it will be the first to incorporate all the major components of a human lung microenvironment critical for fibrosis development (human tissue-tissue interactions, breathing motions, perfusion, and environmental stimuli). Completion of these aims will enable analysis of the mechanism of PF development, with the capability to rapidly repurpose existing FDA- approved drugs as potentially life-saving PF therapeutics.